1. Field of the Invention
The present invention relates to a fusion protein capable of synchronously binding vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha (TNF-α), which are referred to herein as “double anti-inflammation-angiogenesis protein targeting both VEGF-A and TNF-alpha, or ‘Valpha’”. Valpha is disclosed which are therapeutically useful for treating VEGF-A- and TNF-α-associated conditions and diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, diabetic and aged macular degerative retinophaties, cancer, sclerosis, inflammatory bowel disease, polycystic kidney, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and atherosclerosis, and other acute and chronic inflammations.
2. Description of the Background
Vascular endothelial growth factor-A (VEGF-A) plays a crucial role for growth, migration, and survival of blood endothelial cells, which are essential processes for angiogenesis and vasculogenesis mainly through activation of VEGFR1 and VEGFR2 (Ferrara N. et al., Nature Medicine 9:669-676, 2003; Shibuya M and Claesson-Welsh L, Exp. Cell Res. 312:549-560, 2005). VEGF is a prime molecule for tumor angiogenesis and metastasis, abnormal and inflammatory angiogenesis in rheumatoid arthritis, osteoarthritis, psoriasis, diabetic and aged macular degerative retinopathies (Ferrara N. et al., Nature Medicine 9:669-676, 2003; DeBandt M. et al., J Immunol. 171:4853-4859, 2003; Aiello L P. N. Engl. J. Med. 353: 839-841, 2005).
Tumor necrosis factor-alpha (TNF-α) mediates immune response by recruiting leukocyte to the site of inflammation (Hickey M J. et al., J Immunol 158: 3391-3400, 1997). TNF-α is a prime molecule in initiating inflammation through activation of NF-κB in the inflammatory cells including macrophages, endothelial cells and dendritic cells (Rojanasakul Y. et al., Mol. Cell. Biochem. 200: 119-125, 1999).
Elevated levels of VEGF-A and TNF-α are major determinants in diseases related to inflammatory angiogenesis, such as rheumatoid arthritis, osteoarthritis, psoriasis, diabetic and aged macular degerative retinophaties, cancer, sclerosis, inflammatory bowel disease, polycystic kidney, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and atherosclerosis, and other acute and chronic inflammations. Therefore, simultaneous inhibition of VEGF and TNF-α may be more effective than single inhibition of VEGF or TNF-α in treating these diseases.